RBM42

RBM42 is a conserved RNA-recognition-motif protein that couples pre-mRNA splicing to selective translation, acting as a node that links RNA processing to cellular stress responses, cell cycle progression, and development (PMID:37993446, PMID:37294900). In splicing, it engages spliceosome assembly machinery — its orthologs bind sequence motifs in target mRNAs and recruit the U2AF small subunit involved in 3' splice site recognition and interact with tri-snRNP components, a function conserved through human RBM42 by complementation (PMID:23437009, PMID:33976182). During the DNA damage response RBM42 promotes CDKN1A (p21) maturation by counteracting the splicing-inhibitory activity of RBM4, while genome-wide eCLIP shows it binds RNA at both splicing and translation targets, establishing a dual splicing-translation role (PMID:37993446). As a ribosome-associated protein, RBM42 selectively binds and remodels the MYC 5'UTR RNA structure to promote translation pre-initiation complex formation, driving selective translation of MYC, JUN, and EGFR and supporting MYC-dependent tumorigenesis (PMID:31142587, PMID:39905246). RBM42 directly binds hnRNP K and co-relocalizes with it to stress granules under stress, and this interaction is disrupted by a disease-associated RRM variant (PMID:19170760, PMID:37294900). Biallelic loss-of-function in RBM42 causes a human neurodevelopmental syndrome, and Rbm42 mutant mice die in mid-embryogenesis with developmental defects and aberrant alternative splicing (PMID:37294900).

1. 2008 Medium

   Established RBM42 as a physical and functional partner of hnRNP K and a stress-responsive RNA-binding protein, the first mechanistic anchor for the protein.

   Evidence Co-IP, in vitro binding, RNA-IP, RNAi, and co-localization in human cells under stress

   PMID:19170760

   Open questions at the time

   • Did not resolve which RNA-processing step RBM42 acts in
   • Functional consequence of p21 3'UTR binding not defined
   • Stress granule recruitment mechanism unknown
2. 2013 Medium

   Identified RBM42's conserved role in spliceosome assembly and cell cycle progression by showing its Toxoplasma ortholog interacts with tri-snRNP components and is functionally replaceable by human RBM42.

   Evidence Temperature-sensitive mutant, transcriptome profiling, Co-IP with spliceosome components, and complementation with human RBM42

   PMID:23437009

   Open questions at the time

   • Did not define the RNA sequence specificity of RBM42
   • Direct human substrates not mapped
   • Mechanism of spliceosome assembly contribution unresolved
3. 2017 Medium

   Defined RBM42 as an m6A-sensitive RNA binder whose RNA association is disrupted by the modification, placing it among m6A-regulated stress granule factors.

   Evidence Photo-cross-linking chemical proteomics with diazirine m6A RNA probes and quantitative mass spectrometry in vitro

   PMID:29140688

   Open questions at the time

   • In vitro probe binding not validated on endogenous transcripts
   • Cellular consequence of m6A regulation of RBM42 not shown
   • No specific target context defined
4. 2019 Low

   Linked RBM42 to MYC-driven translational control by associating it with 5'UTR motifs governing translation efficiency in lymphoma.

   Evidence Polysome/ribosome profiling and 5'UTR motif RNA-binding analysis in lymphoma cells

   PMID:31142587

   Open questions at the time

   • RBM42's specific molecular contribution not resolved in this study
   • Direct 5'UTR binding not demonstrated structurally
   • Distinct from its splicing role not yet integrated
5. 2021 Medium

   Resolved a sequence-dependent splicing mechanism: the Fusarium ortholog binds a defined motif and recruits the U2AF small subunit to promote 3' splice site recognition, conserved through human RBM42.

   Evidence Deletion mutants, RNA-IP motif mapping, Co-IP with FgU2AF23, complementation with human RBM42, and RNA-seq splicing analysis

   PMID:33976182

   Open questions at the time

   • Human RBM42 motif specificity not directly mapped here
   • Whether U2AF recruitment operates identically in human cells untested
   • No structural basis for motif recognition
6. 2023 High

   Unified RBM42's splicing and translation activities by showing it counteracts RBM4 to promote CDKN1A splicing and translation during DNA damage, with transcriptome-wide direct RNA binding.

   Evidence eCLIP, ribosome profiling, siRNA knockdown, RNA-seq, and RBM4/RBM42 co-depletion epistasis in human cells

   PMID:37993446

   Open questions at the time

   • Molecular basis of RBM4 antagonism not defined
   • How splicing and translation roles are partitioned per transcript unclear
   • Upstream DNA-damage signaling to RBM42 unknown
7. 2024 High

   Established RBM42 as a disease gene: biallelic loss-of-function causes a human neurodevelopmental syndrome, with an RRM variant destabilizing the protein and disrupting hnRNP K binding, and mouse loss causing embryonic lethality with splicing defects.

   Evidence Whole-exome sequencing, in vivo stability assay, Co-IP, Fusarium complementation, mouse compound heterozygous model, and RNA-seq

   PMID:37294900

   Open questions at the time

   • Tissue-specific splicing targets driving phenotype not fully cataloged
   • Genotype-phenotype relationship of variant severity unresolved
   • Whether hnRNP K loss alone explains the syndrome unknown
8. 2025 High

   Mechanistically defined RBM42's translational role: as a ribosome-associated protein it binds and remodels the MYC 5'UTR structure to enable pre-initiation complex formation and selective translation, driving MYC-dependent PDAC tumorigenesis.

   Evidence CRISPRi screen, CLIP-seq, polysome sequencing, IP-MS, DMS-Seq structure probing, mutagenesis, and xenograft models

   PMID:39905246

   Open questions at the time

   • Structural detail of the remodeled 5'UTR not solved
   • How RBM42 partitions between nuclear splicing and ribosomal pools unclear
   • Generality of structure remodeling beyond MYC/JUN/EGFR untested
9. 2025 Medium

   Extended RBM42's translational function to neuronal regeneration, showing IDR-1-driven nuclear export enables dendritic RBM-42 to promote ced-7 translation and microtubule assembly in C. elegans.

   Evidence Forward genetic screen, epistasis, nuclear export and translation reporter assays, and dendrite regeneration imaging (preprint)

   PMID:41332648

   Open questions at the time

   • Preprint, not peer-reviewed
   • Conservation of the IDR-1/RBM-42 axis in mammals untested
   • Mechanism of regulated nuclear export not defined

• How RBM42 is partitioned and switched between its nuclear spliceosome-assembly role and its cytoplasmic ribosome-associated 5'UTR-remodeling role, and how upstream signals (stress, DNA damage, m6A, regulated export) toggle these activities, remains unresolved.
• No structural model of RBM42 RNA recognition
• Regulatory logic coupling splicing and translation undefined
• In vivo m6A regulation of endogenous targets not established